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Paternal alcohol exposure leads to differential expression of sperm miRNA and disrupts offspring growth and metabolism

ABSTRACT: Prenatal development is influenced by various paternal factors, including environmental exposures, lifestyle, and epigenetic modifications. This dissertation investigates the impact of chronic paternal alcohol (EtOH) consumption on offspring development, with a particular focus on placental function, mitochondrial health, and microRNA (miRNA) mediated epigenetic inheritance. Using a previously established mouse model, we explored how preconception paternal alcohol exposure alters sperm-inherited small RNA population and its downstream consequences on placental structure and function. Our findings demonstrate that chronic paternal EtOH consumption induces significant changes in sperm small RNA populations, particularly miRNAs known to regulate early embryonic development. These alterations correlate with disruptions in fetal growth and placental histology, suggesting an intergenerational transmission of stress-induced epigenetic modifications. Furthermore, we identified sex-specific differences in fetoplacental development, where male offspring exhibited pronounced placental inefficiencies and metabolic disruptions. A key aspect of this research involves the role of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of oxidative stress. We show that paternal NRF2 loss-of-function phenocopies the effects of chronic alcohol exposure, reinforcing the hypothesis that oxidative stress-induced epigenetic alterations mediate the observed developmental outcomes. Placental mitochondrial function, a vital determinant of fetal energy supply, was also significantly impaired in alcohol-exposed offspring. Notably, these defects persisted into adulthood, implicating long-term metabolic consequences. To assess the genetic and epigenetic basis of these outcomes, we conducted proteomic and transcriptomic analyses, revealing dysregulated pathways involved in mitochondrial bioenergetics, redox balance, and cellular metabolism. Our results highlight that paternal alcohol exposure not only disrupts placental architecture but also modifies the epigenetic landscape of the developing embryo, leading to systemic physiological alterations. These findings underscore the importance of considering paternal contributions to reproductive health and fetal development. By elucidating the mechanisms underlying alcohol-induced epigenetic inheritance, this research provides novel insights into the role of paternal environmental exposures in shaping offspring health trajectories. Ultimately, this work advocates for broader perspectives on preconception health, emphasizing the need for preventive strategies to mitigate paternal influences on developmental disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE303374 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Adolescent binge alcohol exposure has been previously shown to have long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. Those data suggested that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications. Importantly, epigenetic modifications can be transmitted to future generations therefore, in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore, the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences in the expression of hypothalamic genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure. Male and female Wistar rats were purchased from Charles River Laboratories (Wilmington, MA) at weaning (postnatal day (PND) 23) and allowed to acclimate for 7 days after arrival. Animals were handled for 5 min./once/day beginning at PND 30. Pubertal EtOH exposure began on PND 37, which is defined as peri-puberty. Animals were undisturbed following the first exposure of our binge EtOH exposure paradigm until PND 68 (late puberty/early adult) at which time they received a second exposure to the same treatment paradigm. During the duration of the experiment, males and females were separately housed in pairs on a 12:12 light/dark cycle with lights on at 0700 h with food and water available ad libitum. Binge Exposure Paradigm and Treatment Design. Rats were handled 5min./once/day for 7 d prior to treatment to control for nonspecific stress responses. At 37 d, animals were given 3 g/kg EtOH (20% v/v in tap water; N = 3/sex), or tap water alone (N = 3/sex), once/day via oral gavage at 10:00 AM to avoid disrupting normal feeding patterns. This process was repeated according to the following schedule for a total duration of 8 consecutive days: 3 d EtOH, 2 d tap water, 3 d EtOH. Control animals were given tap water alone once/day for 8 consecutive days. Our previous studies showed that this repeated binge-pattern EtOH paradigm does not affect body weight/growth curves and consistently results in blood alcohol concentrations (BAC) of 150-180 mg/dl in males and 210-240 mg/dl in females. We and others have previously used this paradigm as a model for the pattern of binge alcohol consumption observed in adolescents and BAC achieved are similar to those observed in humans following a binge drinking episode . After peri-pubertal treatments, animals were left undisturbed in their home cage until PND 68 when each group was again exposed to their respective treatment (i.e. control or binge EtOH. We waited 24 hours after the last dose of EtOH to ensure that blood alcohol concentrations in the parents were undetectable at the time of mating (data not shown). Animals were grouped into mating pairs: binge male + binge female (N = 3 pairs); water male + water female (N = 3 pairs). All of the females gave birth to 12-16 pups approximately 28 d after being housed with a male, indicating that conception took place approximately 6 d after pairing; therefore, the pups were never directly exposed to alcohol at any time. At PND 7 pups were deeply anesthetized on ice and sacrificed. Brains were rapidly removed, the hypothalamus microdissected on ice, and then stored in -80ºC until further processing for a genome-wide analysis on hypothalamic total RNA samples using a chip-based microarray (Southern California Genotyping Consortium, SCGC, Illumina Rat Ref-12). The PND 7 time point was chosen because the extent of rat neurodevelopment at PND 7 is roughly equivalent to that of a human infant at birth

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Paternal alcohol exposure leads to differential expression of sperm miRNA and disrupts offspring growth and metabolism

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